This career development award will help fill in the knowledge and skills in vestibular research, an area in which the PI lacks, and is critical for the goal to become an inner ear expert. The goal during the award period is to correlate the molecular events in the inner ear to the neurobehavioral phenotype of the auditory and vestibular system. The long-term objective is to determine the environment leading to vestibular dysfunction in mutant mice, and to apply the information to treat/prevent vestibular dysfunction in humans. The mouse has become a popular animal model for inner ear research due to the feasibility of engineering the genome, and due to cloning of mouse orthologs of genes important for the development and maintenance of hearing and balance in humans. Unlike the auditory function, the vestibular function in most of these mutant mice are not characterized due to technical difficulty of vestibular function analysis in mice. A large knowledge gap exists in determining the mechanisms leading to the vestibular phenotype. In order to characterize the unique molecular environment in each of these mutant mice with vestibular dysfunction, it is important to first accurately assess the type of vestibular dysfunction using a combination of different tests that are adopted for mice. We will perform vestibulo-ocular response (VOR) tests to assess semicircular canal function, as well as utilize a combination of tilt/rocking paradigm in VOR and pseudo-off vertical axis stimulus tests to assess otolith organ function. We will compare the results with mice with unilateral and bilateral vestibular dysfunction to assess the compensation process. We will characterize the inner ear function in caspase-3 deficient mice, a mutant mouse model for vestibular dysfunction. When the proposed studies have been completed, it is our expectation that we will be able to compare basic results of vestibular dysfunction in mice and in human. PUBLIC HEALTH RELEVANCE: The information obtained from the proposed study can be used as basic standards in measurements of vestibular function in other mice models for human vestibular disorders. The similarities and differences in vestibular test results between humans and mice can be utilized to develop prevention and/or treatment methods for vestibular dysfunction and balance disorders.